Phase 1 first-in-human study of anti–ILT3 mAb MK-0482 as monotherapy and in combination with pembrolizumab in advanced solid tumors: Dose escalation results.
Authors: Martin Gutierrez, Anna Spreafico, Ding Wang, Talia Golan, Daniel Renouf, Mark Voskoboynik, Manash Shankar Chatterjee, Kishan J. Kapadia, Qi Liu, Gopala Kovvali, Leah Suttner, Ling Pang, Mei Chen, Anthony W. Tolcher
Journal: Journal of Clinical Oncology (2022)

2505 Background: Immunoglobulin-like transcript 3 (ILT3) is an inhibitory receptor associated with immune tolerance and T-cell suppression within the tumor microenvironment. MK-0482, a novel humanized IgG4 mAb targeting ILT3, is undergoing phase 1 evaluation ± pembrolizumab (pembro) in advanced solid tumors (NCT03918278; MK-0482-001). Dose escalation data are presented. Methods: Eligible patients with advanced solid tumors were enrolled into sequentially escalating dose cohorts of MK-0482 monotherapy (0.2-2250 mg) or MK-0482 (7.5-2250 mg) + pembro 200 mg; both were administered IV Q3W for up to 35 cycles or until progressive disease (PD), unacceptable toxicity, death, or withdrawal. Patients receiving MK-0482 monotherapy could cross over to MK-0482 + pembro after PD. Primary objectives were safety, tolerability, and determination of the recommended phase 2 dose (RP2D). Secondary and exploratory objectives included assessing pharmacokinetics (PK), blood receptor occupancy (RO), anti–drug antibodies (ADA), and objective response rate (ORR) per RECIST v1.1 by investigator assessment. Results: Seventy-five patients were enrolled (n = 29, MK-0482 monotherapy; n = 46, MK-0482 + pembro); 8 patients crossed over to receive the combination. Median age was 63 years (range, 34-86); 73% had ECOG PS 1, 72% received ≥2 lines of prior anticancer therapy, and 32% received prior PD-1/PD-L1 inhibitors. Treatment-related AEs (TRAEs; any-grade/grade 3 or 4) were reported in 34%/7% of patients with MK-0482 monotherapy, 67%/4% with MK-0482 + pembro, and 50%/13% in those who crossed over. The most common TRAEs (≥10% of all patients) were pyrexia (10%) with MK-0482 monotherapy; fatigue (24%) and arthralgia, diarrhea, hyperthyroidism, hypothyroidism, and pruritus (11% each) with MK-0482 + pembro; and arthralgia (25%), hyperthyroidism and hypothyroidism (13% each) for patients who crossed over. Dose-limiting toxicities occurred in 2 patients who received MK-0482 + pembro: 1 grade 5 myositis (MK-0482 750 mg; the only TRAE leading to death) and 1 grade 2 myositis (MK-0482 2250 mg). Preliminary PK and blood RO data suggested that target-mediated drug disposition of MK-0482 was likely saturated in blood mononuclear cells at doses ≥75 mg. ADA to MK-0482 was observed in ̃20% of patients, but no clear impact on MK-0482 PK was observed. A confirmed ORR of 15% (8 PR) was observed in patients who received MK-0482 + pembro, including patients who crossed over; no confirmed responses were observed in patients who received MK-0482 monotherapy. MK-0482 750 mg + pembro was selected as the RP2D based on the totality of data. Conclusions: MK-0482 ± pembro was generally well tolerated, and combination therapy provided modest antitumor activity in patients with heavily pretreated advanced solid tumors. The RP2D of MK-0482 + pembro is under further evaluation in tumor-specific cohorts. Clinical trial information: NCT03918278.